Process for optical resolution of bicyclo[3.3.0]octane-3,7-dione-2 carboxylic acid esters and their 7-monoketals

ABSTRACT

The invention relates to a process for the production of (+)-bicyclo[3.3.0]octan-3-one-2 carboxylic acid steroid esters of formula I ##STR1## in which X means oxygen or the radicals --O--(CH 2 ) n  --O-- or --O--CH 2  --C(CH 3 ) 2  --CH 2  --O--, 
     n means 2 or 3 
     R 2  means hydrogen or methyl, 
     Y means the radicals X or X 1 , 
     X 1  means the radicals OCH 3  or OCOR 3 , 
     R 3  means methyl, ethyl, phenyl, benzyl or pivalyl and the radical ##STR2## the radicals ##STR3## and X and X 1  have the meanings indicated above, characterized in that D,L-bicyclo[3.3.0]octan-3-one-2 carboxylic acid esters of formula II ##STR4## in which X has the meaning indicated above and R is an alkyl group with 1-4 carbon atoms, with optically active steroids with a free 17&#39;beta hydroxy group of formula III ##STR5## in which R 2  and the radical ##STR6## have the meanings indicated above, in the presence of a nucleophilic or acid catalyst is converted into the diastereomeric steroid esters and the optically pure steroid esters of formula I are obtained as crystallizates.

DESCRIPTION

The invention relates to a process for the production of(+)-bicyclo[3.3.0]octan-3-one-2 carboxylic acid steroid esters.

Bicyclo[3.3.0]octane-3,7-dione-2 carboxylic acid esters representimportant intermediate products for the production of carbacyclinderivatives and sesquiterpenes and can easily be produced according to anew process (German patent application P 3702385.3).

It has now been found that in the transesterification of thesebicyclo[3.3.0]octane-3,7-dione-2 carboxylic acid esters with naturallyconfigured steroids, which contain a free 17beta hydroxyl group,surprisingly only the derivatives with the absolute configurationrepresented in formula I crystallize out, while the correspondingdiastereomeric esters IV remain in solution and can be recovered fromthe mother liquors in high optical yields. ##STR7##

The object of the invention is thus the optical resolution of theracemic D,L-bicyclo[3.3.0]octane-3,7-dione carboxylic acid esterderivatives II by transesterification with steroids with a free 17betahydroxyl group, especially with aromatic A ring, of formula III andsubsequent crystallization to steroid esters, and only the enantiomers,with the absolute configuration indicated in general formula I,crystallize out in a nearly optically pure manner, while steroid estersIV, diastereomeric to I, can be recovered in optical yields of about 90%from the mother liquor.

Thus the invention relates to a process for the production of(+)-bicyclo[3.3.0]octan-3-one-2 carboxylic acid steroid esters offormula I ##STR8## in which X means oxygen or the radicals--O--(CH₂)_(n) --O-- or --O--CH₂ --C(CH₃)₂ --CH₂ --O--,

n means 2 or 3

R₂ means hydrogen or methyl,

Y means the radicals X or X₁,

X₁ means the radicals OCH₃ or OCOR₃,

R₃ means methyl, ethyl, phenyl, benzyl or pivalyl and the radical##STR9## and X and X₁ have the meanings indicated above, characterizedin that D,L-bicyclo[3.3.0]octan-3-one-2 carboxylic acid esters offormula II ##STR10## in which X has the meaning indicated above and R isan alkyl group with 1-4 carbon atoms, with optically active steroidswith a free 17beta hydroxy group of formula III ##STR11## in which R₂and the radical ##STR12## have the meanings indicated above, in thepresence of a nucleophilic or acid catalyst is converted into thediastereomeric steroid esters and the optically pure steroid esters offormula I are obtained as crystallizates.

The radicals methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl andtert-butyl are suitable as alkyl groups with 1-4 C atoms.

Estradiol methyl ether as well as compounds of the equilin type or ofthe equilenin type are suitable as steroids of formula III, which carrya 17beta hydroxy group. As further steroids there can be mentioned thosein which gamma=X or X₁.

The preferred reactions are explained by the following diagram I: ThusD,L-bicyclo[3.3.0]octane-3,7-dione-2 carboxylic acid methyl ester VI istransesterified with estradiol methyl ether VII in the presence of4-dimethylaminopyridine (DMAP) or 4-pyrrolidinopyridine (PPY) accordingto the method of D. F. Taber et al., J.O.C. 50, 3618 (1985) or byacid-catalyzed transesterification in the presence of camphorsulfonicacid acid, p-toluenesulfonic acid or methanesulfonic acid in toluene inabout 80-90% yield. In this case, almost optically pure ester VIIIcrystallizes out in 35-40% yield, while the ester (cf. IV)diastereomeric to VIII remains in solution. With the selectiveketalization with neopentyl glycol, VIII yields the steroid ester ketalX. The optically active ketal ester X can also be recovered analogouslyfrom D,L-neopentylketal monoethyl ester IX by transesterification withestradiol methyl ether VII in the presence of DMAP or PPY in crystallineform and practically optically pure in about 35-40% yield, and thediastereomer of X remains in the mother liquor. ##STR13##

Reduction of X with sodium borohydride in methyl tert-butyl ether H₂ Oyields the crystalline alcohol XI, whose optical purity of more than 98%can be determined with the help of HPLC on an analytical acid(ODS-Hypersil) with the system acetonitrilemethanol H₂ O=33:29:38.

Reduction of the amorphous diastereomeric steroid ester obtained in theevaporation of the mother liquor of X with sodium borohydride in methyltert-butyl ether H₂ O yields the diastereomeric crystalline alcohol ofXI, whose optical purity, according to HPLC, is approximately 90%.

Protection of the secondary hydroxyl group of XI with tert-butyldimethyl silyl chloride yields the crystalline silyl compound XII, whichcan be reduced at -78° C. with DIBAH to aldehyde XIII and estradiolmethyl ether VII. After chromatographic separation, VII can be reused.Aldehyde XIII is reacted in the usual way with Wittig-Horner reagentsfor introduction of the lower carbacyclin side chain.

With the excess DIBAH the oily2-hydroxymethyl-3alpha-(dimethyl-tert-butyl-silyloxy)-7-(2,2-dimethyl-1,3-propylenedioxy)-bicyclo[3.3.0]octaneis obtained in 70-90% yield.

A further possibility is the direct introduction of the upper side chainin XIV with the help of a 5-6 times excess of Wittig reagents XV toproduct XVI. The pure 5-E compound XVI, obtained after 5-E/Z separation,can be converted, in an analogous way, to XVII after sodium borohydridereduction, silylation and DIBAH reduction as well as converted to thecarbacyclins XVIII after Wittig-Horner reaction, reduction of the15-keto group and removal of the protecting groups.

In the process for the production of(+)-bicyclo[3.3.0]octan-3-one-2-carboxylic acid steroid esters offormula I catalytic amounts, i.e., 0.01-0.5 molar amounts, preferably0.1 mol of a nucleophilic base, e.g., 4-dimethylaminopyridine,4-pyrrolidinopyridine, 4-piperidinopyridine or polymer-fixed derivativesof these compounds or N-methylimidazole in nonpolar solvents, such as,e.g., dioxane, toluene, xylene, are heated to 80°-160° C., preferably110°-150° C.

Analogously, I can be produced by heating with 0.01-0.05 molar amountsof sulfonic acids such as camphorsulfonic acid, p-toluenesulfonic acidor methanesulfonic acid in toluene.

The invention also comprises (+)-bicyclo[3.3.0]octan-3-one-2 carboxylicacid steroid esters of formula I as valuable intermediate products forthe production of pharmacologically effective carbacyclins of formulaXVIII, such as, e.g., Iloprost, which reduces blood pressure andinhibits thrombocyte aggregation or as biologically valuable derivativesof estradiol methyl ether. Further, compounds I or their diastereomersIV are used as valuable intermediate products for the production ofnatural substances such as sesquiterpenes.

EXAMPLE 1[(+)-3'-methoxy-1',3',5'-estrarien-17'beta-yl]bicyclo[3.3.0]octane-3,7-dione-2-carboxylate

a) 78.48 g (0.4 mol) of D,L-bicyclo[3.3.0]octane-3,7-dione-2 carboxylicacid methyl ester, 114.56 g (0.4 mol) of estradiol-3-methyl ether and4.89 g (0.04 mol) of 4-dimethylaminopyridine (DMAP) were heated in 1200ml of toluene in an oil bath of 130° C. and the resulting methanol inmixture with toluene (distillate=220 ml) was distilled off continuouslyfor 4 hours, and the temperature in the flask rose from 105° C. to 111°C.

After cooling, the dark reaction solution was evaporated in a vacuum andthe residue dissolved in 500 ml of methylene chloride, filtered over acolumn produced with methylene chloride with 400 g of iron-free silicagel and rewashed with 3000 ml of methylene chloride and concentrated byevaporation. The partly crystalline residue (about 200 g) was dissolvedhot in 350 ml of ethyl acetate and allowed to stand overnight forcooling and crystallization. After filtering and washing with ethylacetate, 72.1 g (about 40%) of the title compound with a melting pointof 159°-165° C. was obtained, [α]_(D) =59.5° (C=1, CHCl₃).

b) 1.0 g (0.51 mmol) of D,L-bicyclo[3.3.0]octane-3,7-dione-2 carboxylicacid methyl ester VI, 1.46 g (0.51 mmol) of estradiol methyl ether VIIand 3.4 mg (0.025 mmol) of anhydrous D,L-camphor-10-sulfonic acid areheated with stirring in 20 ml of toluene for 1 hour in an oil bath of125° C. with distilling off of a toluene-methanol mixture. The resultingreaction mixture is filtered over a column, produced with a mixture oftoluene-ethyl acetate (4:1), of 5 g of iron-free silica gel Merck andrewashed with 50 ml of toluene-ethyl acetate mixture (4:1). The eluateis evaporated and the residue is immediately recrystallized from 5 ml ofhot ethyl acetate. A total of 0.828 g (36%) of VII was obtained in twoportions K₁ =0.57 g melting point 169°-171° as well as K₂ =0.258 gmelting point 149°-156°.

EXAMPLE 2[(+)-3'-Methoxy-1',3',5'-estratrien-17beta-yl]-7-(2,2-dimethyl-1,3-propylenedioxy)-bicyclo[3.3.0]octan-3-one-2-carboxylate

a) 50 g (0.177 mol) of(D,L)-7-(2,2-dimethyl-1,3-propylenedioxy)-bicyclo[3.3.0]octan-3-onecarboxylic acid methyl ester, 52.98 g (0.186 mol) of estradiol methylether and 2.16 g (0.0177) of 4-dimethylaminopyridine (DMAP) were heatedin 1000 ml of xylene for 2 hours in an oil bath to 160° C. bathtemperature and at the same time about 440 ml of xylene-methanol mixturewas distilled off. The remaining solvent amount was distilled off in avacuum and the 110 g of brownish residue was filtered, after dissolutionin 1000 ml of methylene chloride, over a column, prepared from methylenechloride, of 600 g of iron-free silica gel (Merck) and rewashed with2500 ml of methylene chloride. After evaporation of the filtrate, 90 gof the oily residue was dissolved in 1100 ml of boiling hexane, filteredand allowed to stand to cool. The crystals (32.8 g) with a melting pointof 100°-110° C. were filtered off and the filtrate was concentrated byPG,15 evaporation to 500 ml, and in cooling another 8.49 g with amelting point of 95°-99° C. precipitated. Thus, altogether 41.7 g(43.5%) was obtained. Recrystallization from hexane yielded 32.8 g (34%)of crystals with a melting point of 116°-120° C.

b) 50 g (110.97 mmol) of the compound obtained according to example 1,12.14 g (116.52 mmol) of 2,2-dimethylpropanediol and 0.734 g (5.55 mmol)of D,L-camphorsulfonic acid as well as 100 g of anhydrous magnesiumsulfate, dried at 200° C. in a vacuum, were stirred in 250 ml of dry,alcohol-free methylene chloride for 18 hours at 24° C., filtered andwashed with methylene chloride. The yellow oil (68.89 g), obtained afterextraction of the filtrate with ice-cold sodium carbonate solution,drying (Na₂ SO₄) and evaporation, was chromatographed with hexane-ether8:2 on a column of 340 g of iron-free silica gel. The first 4 l ofeluate yielded, after evaporation, 43 g (72%) of crude crystalline titlecompound, which yielded from 300 ml of hexane the first portion of 27.38g, melting point 131°-133° C., [α]_(D) =+83° C. (C=1 , CHCl₃) and withconcentration by evaporation of the mother liquor a second portion of3.5 g, melting point 128°-130° C. The total yield was 30.88 g=51.8%.17.3 g of crude initial material could be recoverd by elution of thecolumn win 1.5 l of methanol and evaporation of the eluate.

EXAMPLE 3[(+)-3'-methoxy-estratrien-17'beta-yl]-7-(2,2-dimethyl-1,3-propylenedioxy)-bicyclo[3.3.0]octan-3alpha-ol-2-carboxylate

27.1 g (50.5 mmol) of the compound obtained according to example 2 wassuspended in 1400 ml of freshly distilled methyl tert-butyl ether and5.5 ml of H₂ O and 4.28 g (126.25 mmol) of sodium borohydride is addedwith stirring. After 72 hours stirring, 500 ml of H₂ O was added and theaqueous phase was extracted several times with methylene chloride. Afterdrying (Na₂ SO₄) and evaporation, 28.6 g of the crude product wasobtained, which crystallized after dissolution in 150 ml of methanol at0° C. After filtration and washing with ice-cold methanol, 13.16 g ofcolorless crystals with a melting point of 120°-125° C. was obtained.Concentration of the mother liquor to 60 ml and 40 ml yielded twoadditional portions of 3.71 g, melting point 99°-105° C., and 0.76,melting point 95°-106° C., i.e., a total of 17.57 g (64.6%).Recrystallization from methanol, yielded the pure title compound ofmelting point 139°-140° C., [α]_(D) =+55.2° (C=1, CHCl₃).

EXAMPLE 4[(+)-3'-methoxyestratrien-17'beta-yl]-3alpha-(dimethyl-tert-butyl-silyloxy)-7-(2,2-dimethyl-1,3-propylenedioxy)-bicyclo[3.3.0]octane-2-carboxylate

1 g (1.86 mmol) of the compound obtained according to example 3, 0.47 g(3.06 mmol) of dimethyl-tert-butyl-silyl chloride, 0.25 g (2.04 mmol) of4-dimethylaminopyridine (DMAP) as well as 0.42 ml (3.06 mmol) oftriethylamine were stirred for 18 hours at 24° C., diluted withmethylene chloride and the solution was filtered over 3 g of silica gel.After evaporation of the filtrate, the crystalline residue (1.7 g) wasextracted with 20 ml of hexane and the solution, after filtration, wasevaporated. The residue (1.48 g) was chromatographed on 15 g of silicagel with hexane-ethyl acetate 9:1. The first 200-250 ml of eluate wasevaporated and the residue (1.17 g) was crystallized from 10 ml ofisopropanol, and 0.72 g of colorless crystals with a melting point of94°-97° C. [α]_(D) +27.2° (C=1, CHCl₃) was obtained. Concentration ofthe mother liquor to 3 ml yielded another 0.15 g of colorless crystalswith a melting point of 95°- 98° C. The total yield of the titlecompound was 0.87 g (71.9%).

EXAMPLE 52-Formyl-3alpha-(dimethyl-tert-butylsilyloxy)-7-(2,2-dimethyl-1,3-propylenedioxy)-bicyclo[3.3.0]octane

A solution of 0.5 g (0.766 mmol) of the compound obtained according toexample 4 in 6.5 ml of absolute methylene chloride was instilled in asolution of 1.6 ml (1.915 mmol) of diisobutylaluminum hydride (DIBAH) intoluene at -78° C. within 15 minutes and left for 1 hour at -78° C.After further addition of 1.6 ml (1.915 mmol) of DIBAH solution intoluene it was stirred for another hour at -78° C., then 1.33 ml ofisopropanol was carefully instilled and finally 1.33 ml of H₂ O and 3.5ml of methylene chloride were added. After another hour at 78° C., itwas allowed to warm to 24° C. and the salts were filtered off, whichwere carefully rewashed with methylene chloride. After drying (Na₂ SO₄)and concentration by evaporation, the residue (0.56 g) waschromatographed on a column of 17 g of silica gel with hexane-ethylacetate 95:5, and 90 g (32%) of pure colorless oily title compound wasisolated.

Elution of the SiO₂ column with methanol, extraction with hexane,yielded, after crystallization, 170 mg of pure crystalline estradiolmethyl ether.

With excess DIBAH there was obtained in 70-90% yield, instead of thetitle compound, the oily2-hydroxymethyl-3alpha(dimethyl-tert-butylsilyloxy)-7-(2,2-dimethyl-1,3-propylenedioxy)-bicyclo[3.3.0]octane.

What is claimed is:
 1. A process for the production of(+)-bicyclo[3.3.0]octan-3-one-2 carboxylic acid steroid esters offormula I and its diastereomeric steroid ester of formula IV ##STR14##in which X means oxygen or the radicals --O--(CH₂)_(n) --O-- or --O--CH₂--C(CH₃)₂ --CH₂ --O--,n means 2 or 3 R₂ means hydrogen or methyl, Ymeans the radicals X or X₁, X₁ means the radicals OCH₃ or OCOR₃, R₃means methyl, ethyl, phenyl, benzyl or pivalyl, andthe radical ##STR15##and X and X₁ have the meanings indicated above, characterized in that aD,L-bicyclo[3.3.0]octan-3-one-2 carboxylic acid ester of formula II##STR16## in which X has the meaning indicated above and R is an alkylgroup with 1-4 carbon atoms, is transesterified with an optically activesteroid with a free 17'beta hydroxy group of formula III ##STR17## inwhich R₂ and the radical ##STR18## have the meanings indicated above, inthe presence of a nucleophilic or acid catalyst, wherein the opticallypure steroid esters of formula I can be recovered from the mother liquorin crystalline form.
 2. Process according to claim 1, wherein estradiolmethyl ether is used as optically active steroid of formula III. 3.Process according to claim 1, wherein there are heated to 80°-160° C. asnucleophilic catalyst 4-dimethylaminopyridine, 4-pyrrolidinopyridine,4-piperidinopyridine or the polymer-fixed derivatives of these bases orN-methylimidazole or, with the acid catalysts, camphor sulfonic acid,p-toluene sulfonic acid or methanesulfonic acid in nonpolar solvents. 4.(+)-Bicyclo[3.3.0]octan-3-one-2 carboxylic acid steroid ester of formulaI ##STR19## in which X means oxygen or the radicals --O--(CH₂)_(n) --O--or --O--CH₂ --C(CH₃)₂ --CH₂ --O--,n means 2 or 3 R₂ means hydrogen ormethyl, Y means the radicals X or X₁, X₁ means the radicals OCH₃ orOCOR₃, R₃ means methyl, ethyl, phenyl, benzyl or pivalyl, and theradical ##STR20## and X and X₁ have the meanings indicated above. 5.[(+)-3'-Methoxy-1',3',5'-estratrien-17'beta-yl]-bicyclo[3.3.0]octane-3,7-dione-2-carboxylate,a compound of claim
 4. 6.[(+)-3'-Methoxy-1',3',5'-estratrien-17'beta-yl]-7-(2,2-dimethyl-1,3-propylenedioxy)-bicyclo[3.3.0]octan-3-one-2-carboxylate,a compound of claim
 4. 7. Bicyclo[3.3.0]octan-3-one-2 carboxylic acidsteroid ester of formula IV, in whichX means oxygen or the radicals--O--(CH₂)_(n) --O-- or --O--CH₂ --C(CH₃)₂ --CH₂ --O--, n means 2 or 3R₂ means hydrogen or methyl, Y means the radicals X or X₁, X₁ means theradicals OCH₃ or OCOR₃, R₃ means methyl, ethyl, phenyl, benzyl orpivalyl, and the radical ##STR21## and X and X₁ have the meaningsindicated above.
 8. A process of claim 1, which further comprisesconverting a (+)-bicyclo[3.3.0]octan-3-one-2 carboxylic acid steroidester produced by the process of claim 1 into a carbacyclin by reducingthe ester group to an aldehyde and reacting the aldehyde withWittig-Horner reagents to add a lower carbacyclin side chain.
 9. Aprocess of claim 8, which further comprises converting a(+)-bicyclo[3.3.0]octan-3-one-2 carboxylic acid steroid ester producedby the process of claim 1 into a carbacyclin by reducing the ketonegroup of the ester to a secondary hydroxy group, protecting thesecondary hydroxy group of the ester with a silyl compound, reducing theester group to an aldehyde and reacting the aldehyde with Wittig-Hornerreagents to add a lower carbacyclin side chain.
 10. A process of claim8, wherein the carbacyclin is Iloprost, a pharmacologically effectivecarbacyclin.